QUASAR: A Study to Learn How Well a Higher Amount of Aflibercept Given as an Injection Into the Eye Works and How Safe it is in People With Reduced Vision Due to Swelling in the Macula, Central Part of the Retina Caused by a Blocked Vein in the Retina (Macula Edema Secondary to Retinal Vein Occlusion)

Sponsor

Bayer (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05850520

Collaborator

Regeneron Pharmaceuticals (Industry)

822

Enrollment

312

Locations

Arms

24.2

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Researchers are looking for a better way to treat people who have macular edema secondary to retinal vein occlusion (RVO).

In people with RVO, a blood vessel that carries blood away from the retina (vein) becomes blocked. The retina is the very back part of the eye. The blocked vein causes fluid and blood to leak into the retina and thereby causes a swelling of the macula (the center of the retina responsible for fine vision). This swelling is called macular edema.

When a vein in the retina is blocked, the levels of a protein called vascular endothelial growth factor (VEGF) rises. VEGF helps the growth of new blood vessels. This can lead to macular edema and may cause the vision to become blurry.

The study treatment intravitreal (IVT) aflibercept is given as an injection into the eye. It works by blocking VEGF and this can help repair vision problems related to RVO. IVT aflibercept is already available and is prescribed by doctors as the standard of care treatment for macula edema secondary to RVO. Standard of care is a treatment that medical experts consider most appropriate for a disease.

Standard of care is given every 4 weeks in people with macula edema secondary to RVO. While repeated injections of aflibercept may prevent worsening of vision, it may place a burden on the patient. However, a higher amount (8 mg) compared to the standard of care (2 mg) of IVT aflibercept is being tested in studies. This higher amount could be given less often. The amount of IVT aflibercept given is measured in milligrams, also known as mg.

The main purpose of this study is to learn how well a higher amount of the study treatment aflibercept works in people with macular edema secondary to RVO. To answer this, researchers will measure changes in vision called best corrected visual acuity (BCVA) in the study participants between study start and after 36 weeks of treatment. Changes will then be compared between those participants who received the higher amount of IVT aflibercept and those that received standard of care.

To learn how safe the study treatment is in the participants, the researchers will count the number of participants from study start and up to 64 weeks later that have:

adverse events
serious adverse events

"Adverse events" are any medical problems that the participants have during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think they might be related to the study treatments. An adverse event is considered "serious" when it leads to death, puts the participants' lives at risk, requires hospitalization, causes disability, causes a baby being born with medical problems or is otherwise medically important.

Dependent on the treatment group, the participants will either receive the higher amount of aflibercept or standard of care as an intravitreal injection for up to 60 weeks. The study will consist of a test (screening) phase, a treatment phase and an end of study phase. Each participant will be in the study for up to 64 weeks.

One visit to the study site is planned during the screening phase, followed by visits approximately every 4 weeks (16 in total) during treatment and one visit at the end of the study.

During the study, the study doctors and their team will:

check patients' eye health using various eye examination techniques
measure patients' eye vision (BCVA)
take blood and urine samples
do physical examinations
check vital signs
examine heart health using electrocardiogram (ECG)
do pregnancy tests in women of childbearing age

In addition, participants will be asked to fill a questionnaire on vision-related quality of life.

Condition or Disease	Intervention/Treatment	Phase
Macular Edema Secondary to Retinal Vein Occlusion	Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg Drug: Sham Diagnostic Test: Fluorescein	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

822 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Randomized, Double-Masked, Active-Controlled, Phase 3 Study of the Efficacy and Safety of Aflibercept 8 mg in Macular Edema Secondary to Retinal Vein Occlusion

Anticipated Study Start Date :

May 9, 2023

Anticipated Primary Completion Date :

Nov 29, 2024

Anticipated Study Completion Date :

May 16, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Higher Dose Regimen 1 Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response.	Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose Intravitreally (IVT) injection. Drug: Sham Sham procedure will be given on visits when an active injection is not planned. Diagnostic Test: Fluorescein Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.
Experimental: Higher Dose Regimen 2 Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response.	Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose Intravitreally (IVT) injection. Drug: Sham Sham procedure will be given on visits when an active injection is not planned. Diagnostic Test: Fluorescein Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.
Active Comparator: Standard of care Aflibercept 2 mg is administered by standard treatment intervals, followed by adjustment of treatment intervals according to treatment response.	Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg Intravitreally (IVT) injection. Diagnostic Test: Fluorescein Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.

Arm

Intervention/Treatment

Experimental: Higher Dose Regimen 1

Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response.

Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose

Intravitreally (IVT) injection.

Drug: Sham

Sham procedure will be given on visits when an active injection is not planned.

Diagnostic Test: Fluorescein

Fluorescein 100 mg/mL solution for injection is a dye that makes the retinal vessels visible during FA examinations, and as such, it will be used as an auxiliary medicinal product (AxMP) in this periodic ophthalmic examination. This medicine is for diagnostic use only. It is not used to treat any condition.

Experimental: Higher Dose Regimen 2

Higher dose of aflibercept is administered with initial initiation doses intervals, followed by extension of treatment intervals and further adjustment of intervals according to treatment response.

Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_higher dose

Intravitreally (IVT) injection.

Drug: Sham

Sham procedure will be given on visits when an active injection is not planned.

Diagnostic Test: Fluorescein

Active Comparator: Standard of care

Aflibercept 2 mg is administered by standard treatment intervals, followed by adjustment of treatment intervals according to treatment response.

Drug: Aflibercept, VEGF Trap-Eye(Eylea, BAY86-5321)_2 mg

Intravitreally (IVT) injection.

Diagnostic Test: Fluorescein

Outcome Measures

Primary Outcome Measures

Change from baseline in BCVA measured by the ETDRS letter score at Week 36 [At Week 36]

Secondary Outcome Measures

Number of active injections from baseline to Week 64 [From baseline to Week 64]
Number of active injections from baseline to Week 36 [From baseline to Week 36]
Change from baseline in BCVA measured by the ETDRS letter score at Week 44 [At baseline, week 44]
Change from baseline in BCVA measured by the ETDRS letter score at Week 64 [At baseline, week 64]
Number of participants gaining at least 15 letters in BCVA from baseline at Weeks 36 and 64 [From baseline at week 36 and week 64]
Number of participant achieving an ETDRS letter score of at least 69 (approximate 20/40 Snellen equivalent) at Weeks 36 and 64 [At week 36 and week 64]
Participant having no IRF and no SRF in the center subfield at Weeks 36 and 64 (yes/no) [At week 36 and week 64]
Change from baseline in CST at Weeks 36 and 64 [At baseline, week 36 and week 64]
Change from baseline in NEI VFQ 25 total score at Weeks 36 and 64 [At baseline, week 36 and week 64]
Number of participant with TEAEs and SAEs through Weeks 36 and 64 [Through weeks 36 and 64]
Participants dosed only Q8W through Week 36 in the 8 mg Q8W group [Through weeks 36]
Participants having last treatment intervals ≥12 or of 16 weeks at Week 64 [At week 64]
Participants having next intended interval ≥12 or of 16 weeks at Week 64 [At week 64]
Systemic exposure to aflibercept as assessed by plasma concentrations of free, adjusted bound and total aflibercept from baseline through Weeks 36 and 64 [From baseline through weeks 36 and 64]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult ≥18 years of age (or country's legal age of adulthood if the legal age is >18 years) at the time of signing the informed consent.
Treatment-naïve macular edema involving the foveal center secondary to RVO (BRVO, HRVO, or CRVO) diagnosed within 16 weeks (112 days) before the screening visit in the study eye.
Early Treatment Diabetic Retinopathy Study BCVA letter score of 73 to 24 (20/40 to 20/320) at screening and baseline visits in the study eye.

Decrease in BCVA determined to be primarily the result of RVO in the study eye.

Mean CST ≥300 μm on optical coherence tomography (OCT) if excluding Bruch's membrane (e.g., Cirrus or Topcon) or ≥320 μm if including Bruch's membrane (e.g., Heidelberg Spectralis), confirmed by the reading center at the screening visit and by the site at baseline visit in the study eye.
Capable of giving signed informed consent form (ICF) by study participant or legally acceptable representative, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
US participants will be required to have a Health Insurance Portability and Accountability Act (HIPAA) authorization; in other countries, as applicable according to national laws.
Women of childbearing potential (WOCBP) or men who are sexually active with partners of childbearing potential must agree to use highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last administration of study intervention. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for participation in clinical studies and fulfil the conditions set on Section 10.4.2.

Exclusion Criteria:

Concurrent disease that causes substantial decrease of BCVA, is expected to limit BCVA recovery or is likely to require medical or surgical intervention during the study in the study eye.
Presence or history of the following ocular conditions:

Advanced age-related macular degeneration (neovascular AMD or geographic atrophy) in the study eye.
Diabetic macular edema or diabetic retinopathy, defined in diabetic participants as diabetic retinopathy lesions outside the area of the vein occlusion in the study eye and anywhere in the retina in the fellow eye.
Anterior segment neovascularization, vitreous hemorrhage, retinal detachment in the study eye.
Vitreomacular traction, epiretinal membrane or structural damage to the macula that is considered by the Investigator to significantly affect central vision or preclude improvement in vision in the study eye.
Macular hole of stage 2 and above in the study eye.
Myopia of a spherical equivalent of at least 8 diopters prior to any refractive or cataract surgery in the study eye.
Corneal transplant or corneal dystrophy in the study eye.
Idiopathic or autoimmune uveitis in the study or in the fellow eye.

Presence of the following ocular conditions at screening or baseline visit:

Significant media opacities, including cataract, that interfere with BCVA, or imaging assessments (e.g., fundus photography [FP], OCT) in the study eye.
Aphakia, or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium-aluminum-garnet [YAG] posterior capsulotomy performed more than 30 days before the screening visit), in the study eye.
Uncontrolled glaucoma (defined as IOP >25 mmHg despite treatment with anti-glaucoma medication); or history or likely future need of glaucoma surgery in the study eye.
Intraocular inflammation/infection (including trace, or above, cells in the anterior chamber and/or vitreous) within 12 weeks (84 days) of the screening visit in the study or in the fellow eye.
Extraocular or periocular infection or inflammation (including infectious blepharitis, keratitis, scleritis, or conjunctivitis) in the study or in the fellow eye.

Uncontrolled blood pressure (defined as systolic >160 mmHg or diastolic >95 mmHg) at the screening visit or baseline visit.
Uncontrolled diabetes mellitus, defined by hemoglobin A1c (HbA1c) >12% at the screening visit.
History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) before the screening visit or between screening and baseline visits.
Renal failure requiring dialysis, or renal transplant at screening or potentially during the study.
Any prior or concomitant ocular or systemic treatment (with an investigational or approved, anti-VEGF or other agent) or surgery for RVO in the study eye.
Previous administration of systemic anti-angiogenic medications for any condition.
Prior treatment of the study eye with any of the following drugs (any route of ophthalmic administration) or procedures:

Anti-angiogenic drugs at any time including investigational therapy (e.g., with anti-angiopoietin/anti-VEGF bispecific monoclonal antibodies).
Previous use topical steroids within 4 weeks (28 days) from the screening visit, or intraocular or periocular steroids within 16 weeks (112 days) from the screening visit, or steroid implants at any time.
Previous treatment with intraocular or periocular implant, gene therapy, or cell therapy at any time.
Treatment with ocriplasmin at any time.
Vitreoretinal surgery (including scleral buckling) at any time.
Any intraocular surgery, including cataract surgery, within 12 weeks (84 days) before the screening visit.
Previous treatment with retinal laser photocoagulation.

Prior treatment of the fellow eye with any of the following:

Gene therapy, or cell therapy in the fellow eye at any time.

Participation in other clinical studies requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening visit, or within 30 days or 5 half-lives of administration of the previous study intervention, whichever is longer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina Consultants of Orange County	Fullerton	California	United States	92835
2	Mountain View \| Ophthalmology	Loma Linda	California	United States	92354
3	South Coast Retina Center	Long Beach	California	United States	90807
4	Northern California Retina-Vitreous Associates	Mountain View	California	United States	94040
5	Southern California Desert Retina Consultants	Palm Springs	California	United States	92262
6	California Eye Specialists	Pasadena	California	United States	91107
7	Southern California Permanente Medical Group	Riverside	California	United States	92505
8	Stanford University	Stanford	California	United States	94305
9	Retina Consultants of Southern Colorado, PC	Colorado Springs	Colorado	United States	80909
10	New England Retina Associates	New London	Connecticut	United States	06320
11	Rand Eye Institute	Deerfield Beach	Florida	United States	33064
12	National Ophthalmic Research Institute	Fort Myers	Florida	United States	33912
13	Eye Institute of West Florida	Largo	Florida	United States	33770
14	Florida Eye Associates	Melbourne	Florida	United States	32901
15	Florida Retina Institute	Orlando	Florida	United States	32806
16	Retina Specialists	Pensacola	Florida	United States	32503
17	Fort Lauderdale Eye Institute	Plantation	Florida	United States	33324
18	Retina Vitreous Associates of Florida - Saint Petersburg	Saint Petersburg	Florida	United States	33711-1141
19	East Florida Eye Institute	Stuart	Florida	United States	34994
20	University of South Florida	Tampa	Florida	United States	33612
21	Center for Retina and Macular Disease	Winter Haven	Florida	United States	33880
22	Marietta Eye Clinic	Marietta	Georgia	United States	30060
23	Retina Associates IL	Elmhurst	Illinois	United States	60126
24	University Retina and Macula Associates	Oak Forest	Illinois	United States	60452
25	Retina Associates, LLC	Lenexa	Kansas	United States	66215
26	Retina Care Center	Baltimore	Maryland	United States	21209
27	Cumberland Valley Retina Consultants, PC	Hagerstown	Maryland	United States	21740
28	Mid Atlantic Retina Specialists	Hagerstown	Maryland	United States	21740
29	Vitreo-Retinal Associates, PC	Grand Rapids	Michigan	United States	49525
30	Retina Consultants of Minnesota	Saint Louis Park	Minnesota	United States	55416
31	Retina Consultants of Nevada	Las Vegas	Nevada	United States	89144
32	Sierra Eye Associates	Reno	Nevada	United States	89502
33	Retina Center of New Jersey	Bloomfield	New Jersey	United States	07003
34	NJ Retina	New Brunswick	New Jersey	United States	08901
35	NJ Retina \| Teaneck	Teaneck	New Jersey	United States	07666
36	Eye Associates of New Mexico	Albuquerque	New Mexico	United States	87106
37	Long Island Vitreoretinal Consultants	Great Neck	New York	United States	11021
38	Long Island Vitreoretinal Consultants	Hauppauge	New York	United States	11788
39	Ophthalmic Consultants of Long Island	Lynbrook	New York	United States	11563
40	Retina Associates of Western New York	Rochester	New York	United States	14620
41	Ophthalmic Consultants of the Capital Region	Troy	New York	United States	12180
42	University of NC at Chapel Hill (UNC) Ophthalmology	Chapel Hill	North Carolina	United States	27599
43	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
44	Cincinnati Eye Institute	Cincinnati	Ohio	United States	45242
45	Midwest Retina - Main Office	Dublin	Ohio	United States	43016
46	Retina Consultants, LLC	Salem	Oregon	United States	97302
47	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
48	Mid Atlantic Retina	Philadelphia	Pennsylvania	United States	19107
49	Retina Consultants of Charleston	Charleston	South Carolina	United States	29414
50	Palmetto Retina Center, LLC - Florence	Florence	South Carolina	United States	29501
51	Palmetto Retina Center, LLC	West Columbia	South Carolina	United States	29169
52	Charles Retina Institute	Memphis	Tennessee	United States	38119
53	Austin Retina Associates	Austin	Texas	United States	78705
54	Retinal Consultants of Texas - Bellaire	Bellaire	Texas	United States	77401
55	Texas Retina Associates	Fort Worth	Texas	United States	76104
56	Medical Center Ophthalmology Associates	San Antonio	Texas	United States	78240
57	Retinal Consultants of Texas - San Antonio	San Antonio	Texas	United States	78240
58	Rocky Mountain Retina Consultant	Salt Lake City	Utah	United States	84107
59	The Retina Group of Washington \| Fairfax	Virginia Beach	Virginia	United States	22031
60	Spokane Eye Clinical Research	Spokane	Washington	United States	99204
61	University of Wisconsin - Madison	Madison	Wisconsin	United States	53792
62	Eyeclinic Albury Wodonga	Albury	New South Wales	Australia	2640
63	Marsden Eye Surgery Center	Parramatta	New South Wales	Australia	2150
64	Strathfield Retina Clinic	Strathfield	New South Wales	Australia	2135
65	Sydney Eye Hospital	Sydney	New South Wales	Australia	2000
66	Sydney Retina Clinic	Sydney	New South Wales	Australia	2000
67	Sydney West Retina Pty Ltd	Westmead	New South Wales	Australia	2145
68	Adelaide Eye and Retina Centre	Adelaide	South Australia	Australia	5000
69	Hobart Eye Surgeons	Hobart	Tasmania	Australia	7000
70	Centre for Eye Research	East Melbourne	Victoria	Australia	3002
71	Lions Eye Institute	Nedlands	Western Australia	Australia	6009
72	Klinikum Klagenfurt am Wörthersee	Klagenfurt	Kärnten	Austria	9020
73	Konventhospital Barmherzige Brüder Linz	Linz	Oberösterreich	Austria	4021
74	Medizinische Universität Graz	Graz	Steiermark	Austria	8036
75	Kepler Universitätsklinikum Campus III	Linz		Austria	4021
76	Universitätsklinikum AKH Wien	Wien		Austria	1090
77	Hanusch-Krankenhaus Wien	Wien		Austria	1140
78	SEHAT Pentagram	Sofia		Bulgaria	1309
79	UMHAT Alexandrovska EAD	Sofia		Bulgaria	1431
80	Multiprofile Hospital for Active Treatment Sveta Sofia	Sofia		Bulgaria	1618
81	Specialized Hospital For Active Treatment of Eye Diseases Zora	Sofia		Bulgaria	1784
82	Spec. Hosp. of Ophthalm. Disease for Active Treatment Varna	Varna		Bulgaria	9000
83	The Second Hospital of Anhui medical university	Hefei	Anhui	China	230601
84	Guangzhou Aier Eye Hospital	Guangzhou	Guangdong	China	634050
85	Shijiazhuang General Hospital	Shijiazhuang	Hebei	China	050000
86	Hebei Eye Hospital	Xingtai	Hebei	China
87	Henan Provincial Ophthalmology Hospital (Henan Eye Institute	Zhengzhou	Henan	China	450003
88	Tongji Hosp. of Tongji Med Coll, Huazhong Uni of Sci & Tech.	Wuhan	Hubei	China	430030
89	Renmin Hospital of Wuhan University	Wuhan	Hubei	China	430040
90	The First People's Hospital of Xuzhou	Xuzhou	Jiangsu	China	221002
91	Eye Center of the second Bethune Hospital, jinlin University	Changchun	Jilin	China	130022
92	Shenyang Fourth People's Hospital - Ophthalmology	Shenyang	Liaoning	China	110031
93	Aier Eye Hospital(SHENYANG)	Shenyang	Liaoning	China
94	The People's Hospital of Ningxia Hui Autonomous Region	Yinchuan	Ningxia	China	750000
95	Shanxi Provincial Eye Hospital	Taiyuan	Shaanxi	China	030072
96	The First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi	China	710061
97	Qilu Hospital of Shandong University	Jinan	Shandong	China	250012
98	West China Hospital,Sichuan University	Chengdu	Sichuan	China	610041
99	Aier Eye Hospital (Chengdu)	Chengdu	Sichuan	China
100	ZheJiang Provincial People's Hospital	Hangzhou	Zhejiang	China	310014
101	Dongyang People's Hospital	Jinhua	Zhejiang	China	322199
102	The Affiliated Eye Hospital of Wenzhou Medical College	Wenzhou	Zhejiang	China
103	Beijing Aier Intech Eye Hospital Co. LTD - Ophthalmology	Beijing		China	100021
104	China-Japan Friendship Hospital	Beijing		China	100029
105	Beijing Hospital	Beijing		China	100730
106	Capital Medical University (CMU) - Beijing Tongren Hospital	Beijing		China	100730
107	Peking Union Medical College Hospital CAMS	Beijing		China	100730
108	Peking University First Hospital	Beijing		China
109	Chongqing Aier Ophthalmology Hospital	Chongqing		China	400000
110	The First Affiliated Hospital of Chongqing Medical Universit	Chongqing		China	401147
111	Second Hospital Affiliated of Chongqing Medical University	Chongqing		China
112	Zhejiang University School of Medicine - The First Affiliated Hospital - Kidney Disease Center	Hangzhou		China	310003
113	Lanzhou University - The Second Hospital (The Second Clinical Medical College of Lanzhou University)	Lanzhou		China	730030
114	Eye & Ent Hospital of Fudan University	Shanghai		China
115	China Medical University (CMU) - First Affiliated Hospital	Shenyang		China	110001
116	Tianjin Medical University General Hospital	Tianjin		China	300052
117	Tianjin Medical University Eye Hospital	Tianjin		China	300384
118	TianJin eye hospital	Tianjin		China
119	Fakultni Nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
120	Fakultni nemocnice Ostrava	Ostrava		Czechia	708 52
121	Nemocnice Pardubickeho kraje, a.s., Pardubicka nemocnice	Pardubice		Czechia	53003
122	FN Kralovske Vinohrady	Praha 10		Czechia	10034
123	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	12800
124	Lexum a.s., Evropska ocni klinika	Praha 4		Czechia	140 00
125	AXON Clinical s.r.o.	Praha 5		Czechia	150 00
126	East Tallinn Central Hospital	Tallinn		Estonia	10138
127	Turman Eye Clinic	Tallinn		Estonia	11314
128	Dr. Kai Noor Silmakabinet OU	Tallinn		Estonia	11412
129	Tartu University Hospital	Tartu		Estonia
130	Centre Hospitalier National d'Ophthalmologie Quinze-Vingt	Paris	Cedex 12	France	75557
131	Clinique Rétine Tourny	Bordeaux		France	33000
132	CHU Bordeaux - Hopital Pellegrin - Ophtalmologie	Bordeaux		France	33076
133	Hôpital Intercommunal - Créteil Cedex	Creteil Cedex		France	94010
134	Hôpital François Mitterrand - Dijon	Dijon		France	21000
135	Hôpital de la Croix Rousse	Lyon Cedex 04		France	69317
136	Centre d'Ophtalmologie - Paradis-Monticelli	Marseille		France	13008
137	Clinique Jules Verne - Nantes	Nantes		France	44000
138	Centre d'ophtalmologie de l'Odéon	Paris		France	75006
139	Hôpital Lariboisière - Paris	Paris		France	75010
140	Centre Ophthalmologie d'Imagerie et de Laser	Paris		France	75015
141	CM Wolff	Strasbourg		France	67000
142	Centre Ophtalmologique Transparence - Tours	Tours		France	37000
143	LTD "IQ Clinic"	Tbilisi		Georgia	105
144	LTD Israeli-Georgian Medical Research Clinic "Helsicore"	Tbilisi		Georgia	112
145	LTD "Chichua Medical Center MZERA"	Tbilisi		Georgia	114
146	Caucasus Medical Center- Opthamology	Tbilisi		Georgia
147	Jahn Ferenc Del-Pesti Korhaz es Rendelointezet	Budapest		Hungary	1024
148	MH Egeszsegugyi Kozpont	Budapest		Hungary	1062
149	University of Semmelweis/ Semmelweis Egyetem	Budapest		Hungary	1085
150	Bajcsy Zsilinszky Korhaz-Rendelointezet	Budapest		Hungary	1106
151	Budapest Retina Associates	Budapest		Hungary	1133
152	Debreceni Egyetem Klinikai Kozpont	Debrecen		Hungary	4032
153	Ganglion Medical Center	Pecs		Hungary	7621
154	SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont	Szeged		Hungary	6720
155	Soroka University Medical Center	Beer Sheva		Israel	8410101
156	Rambam Health Corporation	Haifa		Israel	3109601
157	Lady Davis Carmel Medical Center	Haifa		Israel	3436212
158	Edith Wolfson Medical Center	Holon		Israel	5822012
159	Hadassah Hebrew University Hospital Ein Kerem	Jerusalem		Israel	91120
160	Meir Medical Center	Kfar Saba		Israel	4428164
161	Clalit Health Services Rabin Medical Center-Beilinson Campus	Petah Tikva		Israel	4941492
162	Kaplan Medical Center	Rehovot		Israel	7661041
163	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel	6423906
164	Assuta Medical Centers - HaShalom	Tel Aviv		Israel	6789140
165	Shamir Medical Center (Assaf Harofeh)	Zerifin		Israel	7030000
166	Fondazione PTV Policlinico Tor Vergata	Roma	Lazio	Italy	00133
167	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma	Lazio	Italy	00168
168	IRCCS Fondazione G.B. Bietti Studio e Ricerca in Otalmologia	Roma	Lazio	Italy	00198
169	Ospedale San Raffaele s.r.l.	Milano	Lombardia	Italy	20132
170	ASST Fatebenefratelli Sacco	Milano	Lombardia	Italy	20157
171	A.O.U. Ospedali Riuniti "Umberto I - G.M.Lancisi - G.Salesi"	Ancona	Marche	Italy	60126
172	A.O. Ordine Mauriziano	Torino	Piemonte	Italy	10128
173	A.O.U. Consorziale Policlinico	Bari	Puglia	Italy	70124
174	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano		Italy	20122
175	Nagoya City University Hospital	Nagoya	Aichi	Japan	467-8602
176	International University of Health & Welfare Narita Hospital	Narita	Chiba	Japan	286-8520
177	Toho University Sakura Medical Center	Sakura	Chiba	Japan	285-8741
178	University of Fukui Hospital	Yoshida	Fukui	Japan	910-1193
179	Kurume University Hospital	Kurume	Fukuoka	Japan	830-0011
180	Southern Tohoku Eye Clinic	Koriyama	Fukushima	Japan	963-8052
181	Gunma University Hospital	Maebashi	Gunma	Japan	371-8511
182	Hyogo Prefectural Amagasaki General Medical Center	Amagasaki	Hyogo	Japan	660-8550
183	Kobe University Hospital	Kobe	Hyogo	Japan	650-0017
184	Hyogo Medical University Hospital	Nishinomiya	Hyogo	Japan	663-8501
185	Kozawa Eye Hospital and Diabetes Center	Mito	Ibaraki	Japan	310-0845
186	Medical corporation Jiseikai Matsumoto Eye Clinic	Toride	Ibaraki	Japan	302-0014
187	Kagawa University Hospital	Kita-gun	Kagawa	Japan	761-0793
188	Medical corporation Eiwakai Dannoue Ophthalmology clinic	Kawasaki	Kanagawa	Japan	211-0053
189	Yokohama City University Medical Center	Yokohama	Kanagawa	Japan	232-0024
190	Mie University Hospital	Tsu	Mie	Japan	514-8507
191	Shinshu University Hospital	Matsumoto	Nagano	Japan	390-8621
192	National Defense Medical College Hospital	Tokorozawa	Saitama	Japan	359-8513
193	Shiga University of Medical Science Hospital	Otsu	Shiga	Japan	520-2192
194	Shida Eye Clinic	Fujieda	Shizuoka	Japan	426-0029
195	The University of Tokyo Hospital	Bunkyo-ku	Tokyo	Japan	113-8655
196	Nihon University Hospital	Chiyoda-ku	Tokyo	Japan	101-8309
197	Medical corporation Chofu Eye Clinic	Chofu	Tokyo	Japan	182-0024
198	Tokyo Medical University Hachioji Medical Center	Hachioji	Tokyo	Japan	193-0998
199	Tokyo Metropolitan Institute for Geriatrics and Gerontology	Itabashi-ku	Tokyo	Japan	173-0015
200	Tokiwadai Muranaka Eye Clinic	Itabashi-ku	Tokyo	Japan	174-0071
201	National Hospital Organization Tokyo Medical Center	Meguro-ku	Tokyo	Japan	152-8902
202	Keio University Hospital	Shinjuku-ku	Tokyo	Japan	160-8582
203	Tokyo Women's Medical University Hospital	Shinjuku-ku	Tokyo	Japan	162-8666
204	Yamaguchi University Hospital	Ube	Yamaguchi	Japan	755-8505
205	University of Yamanashi Hospital	Chuo	Yamanashi	Japan	409-3898
206	Akita University Hospital	Akita		Japan	010-8543
207	Hayashi Eye Hospital	Fukuoka		Japan	812-0011
208	Murakami Karindoh Hospital	Fukuoka		Japan	819-8585
209	Fukushima Medical University Hospital	Fukushima		Japan	960-1295
210	Kagoshima University Hospital	Kagoshima		Japan	890-8520
211	University of Miyazaki Hospital	Miyazaki		Japan	889-1692
212	Japanese Red Cross Nagasaki Genbaku Hospital	Nagasaki		Japan	852-8511
213	Osaka Metropolitan University Hospital	Osaka		Japan	545-8586
214	Japanese Red Cross Saitama Hospital	Saitama		Japan	330-8553
215	Japanese Red Cross Wakayama Medical center	Wakayama		Japan	640-8558
216	Yamagata University Hospital	Yamagata		Japan	990-9585
217	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggido	Korea, Republic of	463-707
218	Gangnam Severance Hospital, Yonsei University Health System	Seoul	Seoul Teugbyeolsi	Korea, Republic of	06273
219	Pusan National University Hospital	Busan		Korea, Republic of	49241
220	Yeungnam University Medical Center	Daegu		Korea, Republic of	42415
221	Korea University Ansan Hospital	Gyeonggi-do		Korea, Republic of	425-707
222	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
223	Asan Medical Center	Seoul		Korea, Republic of	05505
224	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
225	Samsung Medical Center	Seoul		Korea, Republic of	135-710
226	Kim's Eye Hospital	Seoul		Korea, Republic of	150-034
227	St. Mary Hospital	Seoul		Korea, Republic of	150-713
228	Department of Ophthalmology	Riga		Latvia	1002
229	Riga East Clinical University Hospital "Gailezers"	Riga		Latvia	LV-1006
230	Latvian American Eye Center	Riga		Latvia	LV-1009
231	Hospital of LT University of Health Sciences Kaunas Clinics	Kaunas		Lithuania	LT-50161
232	Vilnius University Hospital Santaros Klinikos	Vilnius		Lithuania	LT-08661
233	Hospital Al-Sultan Abdullah, UiTM \| Opthalmology	Bandar Puncak Alam		Malaysia	42300
234	OasisEye Specialists	Kuala Lumpur		Malaysia	59200
235	Hospital Shah Alam \| Ophthalmology	Shah Alam		Malaysia	40000
236	Hospital Selayang	Shah Alam		Malaysia	68100
237	Fundacion Hospital Nuestra Señora de la Luz	Mexico D. F.	Distrito Federal	Mexico	06030
238	Santa Lucia Clinica \| Oftalmologica	Guadalajara		Mexico	44670
239	FAP Conde de Valenciana, IAP \| Oftalmología	Mexico City		Mexico	06800
240	Hospital Angeles Mocel \| Oftalmologia	Mexico City		Mexico	11850
241	Instituto Mexicano de Oftalmologia, IMO	Queretaro		Mexico	76090
242	Instituto de la Retina del Bajío SC	Queretaro		Mexico	76187
243	Prywatna Klinika Okulistyczna OFTALMIKA	Bydgoszcz		Poland	85-631
244	Specjalistyczny Osrodek Okulistyczny Oculomedica	Bydgoszcz		Poland	85-870
245	NZOZ Poradnia Okulistyczna Dobry Wzrok	Gdansk		Poland	80-402
246	Profesorskie Centrum Okulistyki	Gdansk		Poland	80-809
247	Gabinet Okulistyczny Prof. Edward Wylegala	Katowice		Poland	40-594
248	Centrum Medyczne Dietla 19 Sp. z o.o.	Krakow		Poland	31-070
249	Centrum Medyczne PROMED	Krakow		Poland	31-411
250	Centrum Diagnostyki i Mikrochirurgii Oka Lens	Olsztyn		Poland	10-424
251	Osrodek Chirurgii Oka prof. Zagorskiego Sp. z o.o.	Rzeszow		Poland	35-017
252	Centrum Medyczne Piasta	Walbrzych		Poland	58-304
253	Centro Hospitalar Vila Nova de Gaia/Espinho \| Unit 1 - Clinical Research Office	Vila Nova de Gaia	Porto	Portugal	4434-502
254	AIBILI	Coimbra		Portugal	3000-548
255	Espaco Medico de Coimbra	Coimbra		Portugal	3000-548
256	CHLC - Hospital dos Capuchos - Servico de Oftalmologia	Lisboa		Portugal	1169-050
257	Centro Hospitalar Universitario do Porto	Porto		Portugal	4099-001
258	CHUSJ - Hospital Sao Joao	Porto		Portugal	4200-319
259	Clinical Center of Serbia	Belgrade		Serbia	11000
260	Clinical hospital center Zvezdara	Belgrade		Serbia	11000
261	Klinicki centar Vojvodine	Novi Sad		Serbia	21000
262	Fakultna Nemocnica s poliklinikou F.D.Roosevelta	Banska Bystrica		Slovakia	97517
263	Univerzitna nemocnica Bratislava, Nemocnica Ruzinov	Bratislava		Slovakia	82606
264	Univerzitna nemocnica Bratislava, Petrzalka	Bratislava		Slovakia	851 07
265	Fakultna nemocnica Nitra	Nitra		Slovakia	95001
266	Nemocnica Poprad, a.s.	Poprad		Slovakia	058 45
267	Fakultna nemocnica Trencin	Trencin		Slovakia	911 71
268	Specialized hospital for ophthalmology OPHTAL	Zvolen		Slovakia	960 01
269	Instituto Oftalmológico Francisco Gomez Ulla	Santiago de Compostela	A Coruña	Spain	15706
270	Hospital General de Catalunya	Sant Cugat del Vallés	Barcelona	Spain	08195
271	Hospital Universitario Clinica Puerta de Hierro	Majadahonda	Madrid	Spain	28222
272	Hospital Vall d'Hebron - Servei d'Oftalmologia	Barcelona		Spain	08035
273	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	8036
274	Hospital de la Santa Creu i Sant Pau \| Gynecology Department	Barcelona		Spain	8041
275	Hospital Reina Sofía	Córdoba		Spain	14004
276	Clínica Universidad de Navarra CUN	Pamplona		Spain	31008
277	Hospital General Universitario de Valencia	Valencia		Spain	46014
278	Hospital del Rio Hortega	Valladolid		Spain	47012
279	Hospital Miguel Servet	Zaragoza		Spain	50009
280	RétinElysée	Lausanne	Vaud	Switzerland	1006
281	Inselspital Universitätsspital Bern	Bern		Switzerland	3010
282	Berner Augenklinik am Lindenhofspital	Bern		Switzerland
283	Vista Klinik	Binningen		Switzerland	4102
284	University Eye Hospital Jules Gonin	Lausanne		Switzerland	1004
285	Srinagarind Hospital	Khon Kaen		Thailand	40002
286	Cukurova Universitesi Tip Fakultesi Hastanesi	Adana		Turkey	01330
287	SBU Gulhane Egitim ve Arastirma Hastanesi	Ankara		Turkey	06010
288	Ankara Numune Egitim ve Arastirma Hastanesi	Ankara		Turkey	06100
289	Ankara Universitesi Tip Fakultesi Hastanesi	Ankara		Turkey	06100
290	Hacettepe Universitesi Tip Fakultesi	Ankara		Turkey	06100
291	Baskent Universitesi Tip Fakultesi Hastanesi	Ankara		Turkey	06490
292	Gazi Universitesi Tip Fakultesi	Ankara		Turkey	06500
293	Ankara Bilkent Sehir Hastanesi	Ankara		Turkey	06800
294	Adnan Menderes Universitesi Tip fakultesi	Aydin		Turkey	09100
295	Istanbul Universitesi Istanbul Tip Fakultesi	Istanbul		Turkey	34093
296	Beyoglu Eye Training and Research Hospital	Istanbul		Turkey	34420
297	Ege Universitesi Tip Fakultesi	Izmir		Turkey	35100
298	Kocaeli Universitesi Tip Fakultesi	Kocaeli		Turkey	41380
299	Colchester General Hospital	Colchester	Essex	United Kingdom	CO4 5JR
300	Barnet General Hospital	Barnet	Hertfordshire	United Kingdom	EN5 3DJ
301	Leicester Royal Infirmary	Leicester	Leicestershire	United Kingdom	LE1 5WW
302	James Paget Hospital	Great Yarmouth	Norfolk	United Kingdom	NR31 6LA
303	Frimley Park Hospital NHS	Camberley	Surrey	United Kingdom	GU16 7UJ
304	Epsom General Hospital	Epsom	Surrey	United Kingdom	KT18 7EG
305	Sunderland Eye Infirmary	Sunderland	Tyne And Wear	United Kingdom	SR2 9HP
306	University Hospitals Coventry and Warwickshire NHS Trust	Coventry	West Midlands	United Kingdom	CV2 2DX
307	New Cross Hospital	Wolverhampton	West Midlands	United Kingdom	WV10 0QP
308	St James' University Hospital	Leeds	West Yorkshire	United Kingdom	LS9 7TF
309	Hull and East Yorkshire Eye Hospital Hull and East Yorkshire	Hull	York	United Kingdom	HU3 2JZ
310	Bradford Royal Infirmary	Bradford		United Kingdom	BD9 6RJ
311	Royal Liverpool University Hospital	Liverpool		United Kingdom	L7 8XP
312	Moorfields Eye Hospital	London		United Kingdom	EC1V 2PD